Oily cold water fish, such as salmon, trout, herring, and tuna are the source of dietary marine omega-3 fatty acids, with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) being the key marine derived omega-3 fatty acids. Omega-3 fatty acids have previously been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals. Omega-3 fatty acids have also been shown to improve insulin resistance in obese and non-obese patients with an inflammatory phenotype. Lipid, glucose, and insulin metabolism have been shown to improve in overweight hypertensive subjects through treatment with omega-3 fatty acids. Omega-3 fatty acids (EPA/DHA) have also been shown to decrease triglycerides and to reduce the risk for sudden death caused by cardiac arrhythmias in addition to improve mortality in patients at risk of a cardiovascular event. Omega-3 fatty acids have also been taken as dietary supplements part of therapy used to treat dyslipidemia, and anti-inflammatory properties. A higher intake of omega-3 fatty acids lower levels of circulating TNF-α and IL-6, two of the cytokines that are markedly increased during inflammation processes (Chapkin et al, Prostaglandins, Leukot Essent Fatty Acids 2009, 81, p. 187-191; Duda et al, Cardiovasc Res 2009, 84, p. 33-41). In addition, a higher intake of omega-3 fatty acids has also been shown to increase levels of the well-characterized anti-inflammatory cytokine IL-10 (Bradley et al, Obesity (Silver Spring) 2008, 16, p. 938-944). More recently, there is additional evidence that omega-3 fatty acids could play a significant role in oncology (Anderson et al, Lipids in Health and Disease 2009, 8, p. 33; Bougnoux et al, Progress in Lipid Research 2010, 49, p. 76-86; Erickson et al, Prostaglandins, Leukotrienes and Essential Fatty Acids 2010, 82, p. 237-241). In a study using the xenograft model in nude mice, treatment with omega-3 fatty acids, such as DHA and EPA, resulted in breast tumor regression. Here, treatment with DHA/EPA appeared to increase the level of PTEN protein and attenuate the PI 3 kinase and Akt kinase activity as well as the expression of the anti-apoptotic proteins Bcl-2 and Bcl-XL in the breast tumors (Ghosh-Choudhury, T. et al. Breast Cancer Res. Treat. 2009, 118 (1), 213-228). Additional evidence supporting the use of omega-3 fatty acids in oncology also appeared in a recent study by Lim et al. showing that DHA/EPA could inhibit hepatocellular carcinoma cell growth, presumably by blocking β-catenin and cyclooxygenase-2 (Lim, K. et al. Mol. Cancer Ther. 2009, 8 (11), 3046-3055).
Both DHA and EPA are characterized as long chain fatty acids (aliphatic portion between 12-22 carbons). Medium chain fatty acids are characterized as those having the aliphatic portion between 6-12 carbons. Lipoic acid is a medium chain fatty acid found naturally in the body. It plays many important roles such as free radical scavenger, chelator to heavy metals and signal transduction mediator in various inflammatory and metabolic pathways, including the NF-κB pathway (Shay, K. P. et al. Biochim. Biophys. Acta 2009, 1790, 1149-1160). Lipoic acid has been found to be useful in a number of chronic diseases that are associated with oxidative stress (for a review see Smith, A. R. et al Curr. Med. Chem. 2004, 11, p. 1135-46). Lipoic acid has now been evaluated in the clinic for the treatment of diabetes (Morcos, M. et al Diabetes Res. Clin. Pract. 2001, 52, p. 175-183) and diabetic neuropathy (Mijnhout, G. S. et al Neth. J. Med. 2010, 110, p. 158-162). Lipoic acid has also been found to be potentially useful in treating cardiovascular diseases (Ghibu, S. et al, J. Cardiovasc. Pharmacol. 2009, 54, p. 391-8), Alzheimer's disease (Maczurek, A. et al, Adv. Drug Deliv. Rev. 2008, 60, p. 1463-70) and multiple sclerosis (Yadav, V. Multiple Sclerosis 2005, 11, p. 159-65; Salinthone, S. et al, Endocr. Metab. Immune Disord. Drug Targets 2008, 8, p. 132-42).
Metformin has long been the standard of care treatment for patients with Type 2 Diabetes. It has shown to be anti-atherosclerotic, cardioprotective, has positive effects on vascular endothelium, and suppressant effects on glycation, oxidative stress and in the formation of adhesion molecules. In addition, metformin has shown favorable effects on lipid profiles, reduces liver volume, improves hepatic insulin sensitivity and has positive effects on polycystic ovary syndrome. (Scarpello, J H and Howlett, H C, Diab Vasc Dis Res, 2008, 5(3), 157-167, Nestler, J., New England Journal of Medicine, 2008, 358, p. 47-54). Metformin acts upon the NF-kB axis by increasing the antiangiogenic Thrombospondin-1 (Randeva, H. et al, Cardiovascular Research, 2009, 83, 566-574) as well as by inhibiting P-glycoprotein expression (Jeong, H G e al, British J Pharmacology, 2011, 162(5), 1096-1108). Other guanidine derivatives that have been shown to have anti-diabetic activity include N-methyl-N-guanylglycine, also referred to as creatine. In a comparison study regarding the anti-hyperglycemic effects of creatine (2×3 g a day) and metformin (2×500 mg a day) in recently detected type 2 diabetics, both agents have been shown to elicit similar glucose lowering effects (Rocic et al, Clinical and Investigative Medicine 2009, issue 6, p. E322-E326). Metformin has been used widely since its introduction in the mid 1990's. However, because of its fully protonated form under physiological conditions, it is slowly and incompletely absorbed from the upper intestine upon oral administration. Furthermore, metformin displays some uncomfortable gastrointestinal side effects which sometimes limit patient compliance and effectiveness. Hence, a number of different pro-drug forms of metformin have been investigated. Some of these are detailed in Huttunen et al, Synthesis 2008, p. 3619-3624. Some of these pro-drug forms included carbamate derivatives and rigid phenyl derivatives that allowed 1,6-elimination of either a p-amino or p-hydroxybenzylic group. Other cyclic derivatives of metformin have also been prepared in order to improve its tolerability. These cyclic derivatives of metformin included imeglimin (Wacharine-Antar et al, Org. Process Research & Development 2010, 14, p. 1358-2363) and other compounds disclosed in Helmreich et al's WO 2010108583.
Salicylates and other non-steroidal anti-inflammatory drugs (NSAIDs) can influence the NF-κB pathway, allowing people to derive relief and reduced inflammation from these drugs. Aspirin and COX inhibitors act to reduce inflammation by reversibly or irreversibly blocking access to the hydrophobic channel via acetylation of serine 530 (COX-1) or Serine 516 (COX-2). For some selective NSAIDs with a carboxylate group, there is significant charge-charge interaction with Arginine 120. This binding or interaction blocks the cyclooxygenase enzyme that forms PGH2. Salicylate does not irreversibly inhibit cyclooxygenase because it lacks the ability to acylate the COX enzyme and has little, if any, direct inhibitory action on the COX enzyme at concentrations that are relevant in vivo. Salicylate has been shown to inhibit the activity of IKKβ and thereby inhibit NFκB leading to reduced expression of COX-2 in an inflammatory state where COX-2 expression has been induced.
Because of the ability of guanidine derivatives such as, for example, metformin and omega-3 fatty acid or salicylic acid to act on the NF-κB axis, a synergistic activity would provide a great benefit in treating multiple myeloma, myelodysplastic syndromes (MDS) or other metabolic diseases.